Reactive oxygen species (ROS), such as superoxide, have historically been viewed as harmful metabolic by-products but recent studies have shown that ROS may act as second messengers in signal transduction pathways and as cell-cell signaling molecules. In the search for synaptic retrograde signals, ROS were found to be important in synaptic transmission and long-term potentiation (LTP), a long-lasting synaptic enhancement that may be involved in certain types of mammalian learning and memory. Using the tools of molecular biology, electrophysiology and animal behavior tests, we are beginning to uncover the role of ROS in synaptic transmission, learning and memory. In characterizing the role of reactive oxygen species in synaptic transmission, it will be necessary to examine aspects of ROS production and regulation, ROS protein interactions and signaling effects. Mitochondria are a major source of ROS in neurons and voltage-dependent anion channels (VDACs) may play an important role in regulating ROS efflux. Mice lacking the VDAC genes show a deficit in LTP that appears to be due to decreased intracellular ROS concentration. In addition to characterizing the VDAC knockout mouse, I will determine the downstream effectors involved in ROS signaling during synaptic transmission.